Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment
Authors: Jeroen C. de Jonge, Wouter M. Sluis, Hendrik Reinink, Philip M. Bath, Lisa J. Woodhouse, Berber Zweedijk, Diederik van de Beek, Anne Hege Aamodt, Iris Alpers, Alfonso Ciccone, Laszlo Csiba, Jacques Demotes, Janika Kõrv, Iwona Kurkowska-Jastrzebska, Jesse Dawson, Malcolm R. Macleod, George Ntaios, Sven Poli, Haralampos Milionis, Stefano Ricci, Silvia Cenciarelli, Paolo Candelaresi, Sebastiaan FTM. de Bruijn, Rohan Pathansali, Kailash Krishnan, Brian Clarke, Götz Thomalla, H Bart van der Worp, Henk Kerkhoff, Marieke JH. Wermer, Korné Jellema, Vincent IH. Kwa, Ben P. Jansen, Tobien AHCML. Schreuder, Sanne M. Zinkstok, Walid Moudrous, Katrin Antsov, Katrin Gross-Paju, Inga Kalju, Gerhard F. Hamann, Michael Rosenkranz, Christoph Gumbinger, Georg Royl, Susanne Müller, Sophie Vassilopoulou, Athanasios D. Protogerou, Efstathios Manios, Dániel Bereczki, Gábor Jakab, Ferenc Nagy, András Folyovich, László Szapáry, Nicola Gilberti, Enrico Righetti, Pietro Bassi, Simona Marcheselli, Alessia Giossi, Anne G. Holtan, Sameer Maini, Waldemar Fryze, Waldemar Brola, Piotr Sobolewski, Marta Bilik, Ruth Davies, Anand Nair, Dipankar Dutta, Martin Cooper, Khalid Rashed, Louise Shaw, Johann R. Selvarajah, Jessica Redgrave, Mary Joan MacLeod, Philip Clatworthy, Vasileios Papavasileiou, Vera Cvoro, Omid Halse, Usman Ghani
Journal: The Lancet Regional Health - Europe (2023)

Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke.We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627).From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events.We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke.This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.